To investigate the suppressive function of RO4929097, a potent -secretase inhibitor, on RANKL-induced osteoclastogenesis. The cytotoxicity of RO4929097 was evaluated. The suppressive effect and possible molecular mechanism of RO4929097 on RANKL-induced osteoclastogenesis was evaluated both in vitro and in vivo. The IC50 of RO4929097 was 2.93 μM. Treatment with different doses of RO4929097 (100 nM, 200 nM, and 400 nM) effectively reduced osteoclast formation (number and resorption area) in a dose-dependent manner. The qPCR results revealed that RO4929097 attenuates RANKL-induced osteoclast formation and NFATc1 protein expression. The in vivo experiments demonstrated that RO4929097 had an inhibitory effect on LPS-induced bone resorption. Our in vitro experiments showed that RO4929097 can potently inhibit osteoclastogenesis and bone resorption by down-regulating the Notch/MAPK/JNK/Akt-mediated reduction of NFATc1. In accordance with these in vitro observations, RO4929097 attenuated LPS-induced osteolysis in mice. In conclusion, our findings indicate that Notch may represent a potential therapeutic target for the treatment of osteolytic diseases.Sirtuins have been shown to regulate the aging process. https://www.selleckchem.com/products/namodenoson-cf-102.html We have previously demonstrated that Sirt6 blocks the pressure overload-induced cardiac hypertrophy in mice. Here, we show that Sirt6 can also mitigate aging-induced cardiomyocyte senescence and cardiac hypertrophy. We found that aging is associated with altered Sirt6 activity along with development of cardiac hypertrophy and fibrosis. Compared to young mice (4-months), the hearts of aged mice (24-months) showed increased levels of mitochondrial DNA damage, shortened telomere length, and increased accumulation of 8-oxo-dG adducts, which are hallmarks of aging. The aged hearts also showed reduced levels of NAD+ and altered levels of mitochondrial fusion-fission proteins. Similar characteristics were observed in the hearts of Sirt6 deficient mice. Additionally, we found that doxorubicin (Dox) induced cardiomyocyte senescence, as measured by expression of p16INK4a, p53, and β-galactosidase, was associated with loss of Sirt6. However, Sirt6 overexpression protected cardiomyocytes from developing Dox-induced senescence. Further, compared to wild-type mice, the hearts of Sirt6.Tg mice showed reduced expression of aging markers, and the development of aging-associated cardiac hypertrophy and fibrosis. Our data suggest that Sirt6 is a critical anti-aging molecule that regulates various cellular processes associated with aging and protects the heart from developing aging-induced cardiac hypertrophy and fibrosis.Intracranial aneurysms (IAs) are common cerebrovascular diseases that carry a high mortality rate, and the mechanisms that contribute to IA formation and rupture have not been elucidated. ADAMTS-5 (ADAM Metallopeptidase with Thrombospondin Type 1 Motif 5) is a secreted proteinase involved in matrix degradation and ECM (extracellular matrix) remodeling processes, and we hypothesized that the dysregulation of ADAMTS-5 could play a role in the pathophysiology of IA. Immunofluorescence revealed that the ADAMTS-5 levels were decreased in human and murine IA samples. The administration of recombinant protein ADAMTS-5 significantly reduced the incidence of aneurysm rupture in the experimental model of IA. IA artery tissue was collected and utilized for histology, immunostaining, and specific gene expression analysis. Additionally, the IA arteries in ADAMTS-5-administered mice showed reduced elastic fiber destruction, proteoglycan accumulation, macrophage infiltration, inflammatory response, and apoptosis. To further verify the role of ADAMTS-5 in cerebral vessels, a specific ADAMTS-5 inhibitor was used on another model animal, zebrafish, and intracranial hemorrhage was observed in zebrafish embryos. In conclusion, our findings indicate that ADAMTS-5 is downregulated in human IA, and compensatory ADAMTS-5 administration inhibits IA development and rupture with potentially important implications for treating this cerebrovascular disease.Capsanthin is a naturally occurring red pepper carotenoid with possible antitumor activity, but its antitumor mechanisms have yet to be delineated. We tested the anti-proliferative activity of capsanthin with human triple-negative breast cancer (TNBC) and found that cell proliferation was inhibited after 24, 48 and 72 h of treatment. We also investigated the cellular and molecular mechanisms of the antitumor efficacy of capsanthin on TNBC cells and found that capsanthin delayed cell-cycle progression at the G1/S stage, that cyclin A expression was suppressed, and that p21 expression was upregulated. Capsanthin also inhibited the EZH2 expression and EZH2 could binding to the p21 promoter in TNBC cells. We further discovered that capsanthin has synthetic effects when combined with erlotinib (Tarceva). In the animal experiment, we found that the capsanthin-induced inhibition of TNBC cell proliferation decreased the incidence of the initiation and growth of TNBC cell-derived tumors in mice. Our study reveals that capsanthin exerted antitumor effects through delaying cell-cycle progression, induces erlotinib-sensitivity and inhibits tumor progression by inhibiting EZH2/p21 axis, and capsanthin is a potential drug candidate for development of a safe and effective therapy against TNBCs, especially for TNBCs that have developed resistance to targeting therapy.Összefoglaló. A gyulladásos bélbetegség (inflammatory bowel disease, IBD) incidenciája folyamatosan nő, etiológiája egyelőre ismeretlen. Kezelésében gyakran alkalmazunk immunszuppresszív, illetve immunmoduláns szereket. Egyes esetekben azonban szolidszerv-transzplantációt követően, folyamatos immunszuppresszív kezelés mellett is megfigyelhető de novo IBD kialakulása. Célunk az volt, hogy Klinikánk beteganyagából összesítsük azon eseteket, amelyekben szolid szerv (máj, vese, tüdő) transzplantációját követően de novo IBD alakult ki. A transzplantációt megelőzően szklerotizáló cholangitis miatt gondozott betegeket kizártuk. A Klinikánkon gondozott, szolid szerv transzplantációján (179 máj, 197 vese, 29 tüdő) átesett betegek közül 4 (2 máj- és 2 vesetranszplantált) gyermeknél alakult ki de novo IBD. A transzplantációhoz vezető alapbetegségek biliaris atresia, polycystás vese és Denys-Drash-szindróma voltak. A transzplantációt követő immunszuppresszív terápia mind a 4 esetben tartalmazott szisztémásszteroid- és takrolimuszkezelést, emellett 3 esetben mikofenolát-mofetil (MMF)-terápiát is.